1D Receptor Research Articles

SB-616234-A (1-[6-( cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2′methyl-4′-(5-methyl-1,2,3-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride): A novel, potent and selective 5-HT 1B receptor antagonist

SB-616234-A possesses high affinity for human 5-HT 1B receptors stably expressed in Chinese hamster ovary (CHO) cells (p K i 8.3 ± 0.2), and is over 100-fold selective for a range of molecular targets except h5-HT 1D receptors (p K i 6.6 ± 0.1). Similarly, affinity (p K i) for rat and guinea pig striatal 5-HT 1B receptors is 9.2 ± 0.1. In [ 35S]-GTPγS binding studies in the human recombinant cell line, SB-616234-A acted as a high affinity antagonist with a pA 2 value of 8.6 ± 0.2 whilst providing no evidence of agonist activity in this system. In [ 35S]-GTPγS binding studies in rat striatal membranes, SB-616234-A acted as a high affinity antagonist with an apparent p K B of 8.4 ± 0.5, again whilst providing no evidence of agonist activity in this system. SB-616234-A (1 μM) potentiated electrically stimulated [ 3H]-5-HT release from guinea pig and rat cortical slices (S 2/S 1 ratios of 1.8 and 1.6, respectively). SB-616234-A (0.3–30 mg kg −1 p.o.) caused a dose-dependent inhibition of ex vivo [ 3H]-GR125743 binding to rat striatal 5-HT 1B receptors with an ED 50 of 2.83 ± 0.39 mg kg −1 p.o. Taken together these data suggest that SB-616234-A is a potent and selective 5-HT 1B autoreceptor antagonist that occupies central 5-HT 1B receptors in vivo following oral administration.

New targets in acute migraine treatment

Migraine is a common and highly disabling neurological problem, whose acute treatment was revolutionized by the triptans, serotonin 5-HT1B/1D receptor agonists. Some patients do not respond to triptans, while others are not suitable for them largely because of contraindications based on vascular disease. The exploration of nonvasoconstrictor treatments for acute migraine offers the prospect of dramatic improvements in patient care, as well as important insights into the mechanisms of migraine. Possibilities for such developments include, calcitonin gene-related peptide receptor antagonists, serotonin 5-HT1F and 5-HT1D receptor agonists, glutamate excitatory amino acid receptor antagonists, nitric oxide synthase inhibitors and adenosine A1 receptor agonists. Taken together, the future for migraine and affected patients is bright and promising.

Effect of simulated microgravity on vascular α adrenoceptor function

The goal of the present study was to determine the effects of microgravity on vascular α adrenoceptor (α AR) function. Microgravity was simulated using classical hindlimb unweighting in rats and abdominal aorta (AA) rings were isolated after 20 days for α AR functional analysis. Norepinephrine (NE) concentration-contractile response curves (CRCs) were obtained before and after partial receptor inactivation (3 nM phenoxybenzamine, 5 minutes). The CRCs were analyzed to determine affinity (KA) and efficacy (percent receptor occupancy at 50% of maximal contraction; EC50). NE EC50 values in C and HU AA, 7.65±0.1 and 7.7±0.1 and KA values, 6.15±0.2 and 6.14±0.2, respectively, were not significantly different. Efficacy was high in both C and HU AA: 1.83 and 1.7% receptor occupancy at EC50, respectively. Similar results were obtained using phenylephrine (PHE) as the agonist. Real time RT-PCR revealed a significant decrease in the α1B receptor gene expression in HU vs. C; 1A and 1D receptors trended toward increase. NE CRCs were right-shifted by 0.1 μM rauwolscine equally in C and HU AA. The contributions of both α1 and α2 ARs may explain Hill slopes of 0.23 and 0.27 in C and HU, respectively. The Hill slopes for the α1 AR selective agonist, PHE, were 0.57 and 0.6, respectively. It was concluded that HU had no effect on AA α AR function. NASA Grant NNA04CK29G

SB-649915, a novel, potent 5-HT 1A and 5-HT 1B autoreceptor antagonist and 5-HT re-uptake inhibitor in native tissue

An increase in brain 5-HT levels is thought to be the key mechanism of action which results in an antidepressant response. It has been proven that selective serotonin re-uptake inhibitors are effective antidepressants but the delay to therapeutic onset of these agents is thought to be due to the time required for 5-HT 1A, and possibly 5-HT 1B, autoreceptor desensitisation. Therefore an agent incorporating 5-HT re-uptake inhibition coupled with 5-HT 1A and/or 5-HT 1B autoreceptor antagonism may provide a fast acting clinical agent. The current studies describe the in vitro profile of SB-649915 (6-[(1-{2-[(2-methylquinolin-5-yl)oxy]ethyl}piperidin-4-yl)methyl]-2 H-1,4-benzoxazin-3(4 H)-one), a novel compound which has high affinity for human recombinant 5-HT 1A, 5-HT 1B and 5-HT 1D receptors (p K i values of 8.6, 8.0, 8.8, respectively) and the human recombinant 5-HT transporter (p K i value of 9.3). SB-649915 also displays high affinity for rat, guinea pig, mouse and marmoset native tissue 5-HT 1A, 5-HT 1B and 5-HT 1D receptors and rat native tissue 5-HT transporters (p K i values ≥ 7.5). In functional [ 35S]GTPγS binding studies, SB-649915 (up to 1 μM) does not display intrinsic activity in HEK293 cells expressing human recombinant 5-HT 1A receptors but acts as a partial agonist at human recombinant 5-HT 1B and 5-HT 1D receptors with intrinsic activity values of 0.3 and 0.7, respectively, as compared to the full agonist 5-HT. From Schild analysis, SB-649915 caused a concentration-dependent, rightward shift of 5-HT-induced stimulation of basal [ 35S]GTPγS binding in cells expressing human recombinant 5-HT 1A or 5-HT 1B receptors to yield p A 2 values of 9.0 and 7.9, respectively. In electrophysiological studies in rat dorsal raphe nucleus, SB-649915 did not affect the cell firing rate up to 1 μM but attenuated (+)8-hydroxy-2-(di- n-propylamino) tetralin-induced inhibition of cell firing with an apparent p K b value of 9.5. SB-649915 (1 μM) significantly attenuated exogenous 5-HT-induced inhibition of electrically-stimulated [ 3H]5-HT release from guinea pig cortex. In studies designed to enhance endogenous 5-HT levels, and therefore increase tone at 5-HT 1B autoreceptors, SB-649915 significantly potentiated [ 3H]5-HT release at 100 and 1000 nM. In LLCPK cells expressing human recombinant 5-HT transporters and in rat cortical synaptosomes, SB-649915 inhibited [ 3H]5-HT re-uptake with pIC 50 values of 7.9 and 9.7, respectively. In summary, SB-649915 is a novel, potent 5-HT 1A/1B autoreceptor antagonist and 5-HT re-uptake inhibitor in native tissue systems and represents a novel mechanism that could offer fast acting antidepressant action.

Nitric oxide-evoked glutamate release and cGMP production in cerebellar slices: Control by presynaptic 5-HT 1D receptors

We previously reported that pre- and postsynaptic 5-hydroxytryptamine (5-HT) receptors effectively control glutamatergic transmission in adult rat cerebellum. To investigate where 5-HT acts in the glutamate ionotropic receptors/nitric oxide/guanosine 3′,5′-cyclic monophosphate (cGMP) pathway, in the present study 5-HT modulation of the cGMP response to the nitric oxide donor S-nitroso-penicillamine (SNAP) was studied in adult rat cerebellar slices. While cGMP elevation produced by high-micromolar SNAP was insensitive to 5-HT, 1 μM SNAP, expected to release nitric oxide in the low-nanomolar concentration range, elicited cGMP production and endogenous glutamate release both of which could be prevented by activating presynaptic 5-HT 1D receptors. Released nitric oxide appeared responsible for cGMP production and glutamate release evoked by 1 μM SNAP, as both the effects were mimicked by the structurally unrelated nitric oxide donor 2-( N, N-diethylamino)-diazenolate-2-oxide (0.1 μM). Dependency of the 1 μM SNAP-evoked release of glutamate on external Ca 2+, sensitivity to presynaptic release-regulating receptors and dependency on ionotropic glutamate receptor functioning, suggest that nitric oxide stimulates exocytotic-like, activity-dependent glutamate release. Activation of ionotropic glutamate receptors/nitric oxide synthase/guanylyl cyclase pathway by endogenously released glutamate was involved in the cGMP response to 1 μM SNAP, as blockade of NMDA/non-NMDA receptors, nitric oxide synthase or guanylyl cyclase, abolished the cGMP response. To conclude, in adult rat cerebellar slices low-nanomolar exogenous nitric oxide could facilitate glutamate exocytotic-like release possibly from parallel fibers that subsequently activated the glutamate ionotropic receptors/nitric oxide/cGMP pathway. Presynaptic 5-HT 1D receptors could regulate the nitric oxide-evoked release of glutamate and subsequent cGMP production.

Mechanisms of action of current and potential pharmacotherapies of obsessive-compulsive disorder

A significant body of evidence documented that the orbitofrontal cortex (OFC) and the head of caudate nucleus are involved in the mediation of obsessive-compulsive disorder (OCD) symptoms. Potent serotonin (5-HT) reuptake inhibitors (SRIs) are the only antidepressant agents thus far shown to be effective in the treatment of OCD. The present review summarizes information on 5-HT release and the adaptive changes in pre- and postsynaptic 5-HT receptors sensitivity induced by SRI treatment in rat and guinea pig structures involved in OCD. It emphasizes that the time course for the occurrence of increased 5-HT release and terminal 5-HT 1D desensitization is congruent with the delayed therapeutic response to SRI in OCD. In addition, a greater dose of SRI inducing a greater degree of reuptake inhibition may play an essential role in this phenomenon. This is consistent with the common clinical observation that high doses of SRIs are sometimes necessary to obtain an anti-OCD effect, and with the results of some fixed-dose double blind trials showing a dose-dependent therapeutic effect of SRIs. It is hypothesized that enhanced 5-HT release in the OFC is mediated by the activation of normosensitive postsynaptic 5-HT 2-like receptors and underlies the therapeutic action of SRI in OCD. This is supported by the beneficial effect of some hallucinogens with 5-HT 2 agonistic properties in obtaining a more rapid therapeutic response. Finally, based on this knowledge, new strategies aimed at producing more rapid, effective and safe anti-OCD drugs, such as a selective action on terminal 5-HT 1D receptors, on 5-HT 2 receptors as well as on the glutamate system, are discussed.

Expression mapping of 5-HT1 serotonin receptor subtypes during fetal and early postnatal mouse forebrain development

Serotonin (5-HT) is implicated in several aspects of brain development, yet the ontogenetic expression patterns of 5-HT receptors responsible for transducing specific effects have largely not been characterized. Fifteen different 5-HT receptor genes have been cloned; therefore any spatial and/or temporal combination of their developmental expression could mediate a wide array of 5-HT effects. We undertook a detailed analysis of expression mapping of the Gi/o-coupled 5-HT1 (5-HT1A, 1B, 1D and 1F) receptor subtypes in the fetal and early postnatal mouse forebrain. Using receptor subtype-specific riboprobes and in situ hybridization, we observed that all 5-HT1 receptor subtypes are expressed as early as embryonic day (E) 14.5 in the forebrain, typically in gradients within specific structures. Among 5-HT1 receptors, the 5-HT1A receptor transcript is expressed densely in E14.5–16.5 thalamus, in hippocampus, and in a medial to lateral gradient in cortex, whereas the 5-HT1B receptor mRNA is expressed in more lateral parts of the dorsal thalamus and in the striatum at these ages. The 5-HT1D receptor transcript, which also is expressed heavily in E14.5–E16.5 thalamus, appears to be down-regulated at birth. The 5-HT1F receptor transcript is present in proliferative regions such as the cortical ventricular zone, ganglionic eminences, and medial aspects of the thalamus at E14.5–16.5, and otherwise presents similarities to the expression patterns of 5-HT1B and 1D receptor transcripts. Overall, the 5-HT1 subfamily of Gi/o-coupled 5-HT receptors displays specific and dynamic expression patterns during embryonic forebrain development. Moreover, all members of the 5-HT1 receptor class are strongly and transiently expressed in the embryonic dorsal thalamus, which suggests a potential role for serotonin in early thalamic development.

Effects of 5-HT1B/1D Receptor Agonist Rizatriptan on Cerebral Blood Flow and Blood Volume in Normal Circulation

To investigate the vasoconstrictor effect of 5-hydroxytryptamine (5-HT1B/1D) receptor agonists for migraine treatment, changes in cerebral blood flow (CBF) and blood volume induced by rizatriptan were assessed by positron emission tomography (PET). Eleven healthy volunteers underwent PET studies before and after rizatriptan administration. Dynamic PET data were acquired after bolus injection of H2(15)O to analyze CBF and arterial-to-capillary blood volume (V0) images using the three-weighted integral method. After a baseline scan, three further acquisitions were performed at 40 to 50, 60 and 70 to 80 mins after drug administration. Global and regional differences in CBF and V0 between conditions were compared using absolute values in the whole brain and cortical regions, as well as statistical parametric mapping (SPM) analysis. The global and regional values for CBF and V0 decreased significantly after rizatriptan administration compared with the baseline condition. However, both values recovered to baseline within 80 mins after treatment. The maximal reduction in global CBF and V0 was approximately 13% of baseline value. The greatest decrease in CBF was observed approximately 60 mins after drug administration, whereas the maximal reduction in V0 was observed approximately 5 mins earlier. Statistical parametric mapping did not highlight any regional differences between conditions. Thus, in brain circulation, rizatriptan caused significant CBF and V0 decreases, which are consistent with the vasoconstrictor effect of triptans on the large cerebral arteries. The gradual recovery in the late phase from the maximal CBF and V0 decrease suggests that rizatriptan does not affect the cerebral autoregulatory response in small arteries induced by CBF reduction.

Tanacetum parthenium and Salix??alba??(Mig-RL??) Combination in??Migraine Prophylaxis

Tanacetum parthenium (feverfew) has been used traditionally to treat migraine, and although its mechanism of action is not fully understood, serotonin 5-HT receptor blocking effects have been suggested. T. parthenium and Salix alba (white willow) either alone or in combination (Mig-RL) were recently shown to inhibit binding to 5-HT(2A/2C) receptors; T. parthenium failed to recognise 5-HT(1D) receptors, whereas S. alba or the combination did. It was hypothesised that S. alba in combination with T. parthenium may provide superior migraine prophylactic activity compared with T. parthenium alone. A prospective, open-label study was performed in 12 patients diagnosed with migraine without aura. Twelve weeks' treatment with T. parthenium 300 mg plus S. alba 300 mg (Mig-RL) twice daily was administered to determine the effects of therapy on migraine attack frequency (primary efficacy criterion), intensity and duration (secondary efficacy criteria), and quality of life, together with tolerability for patients. Attack frequency was reduced by 57.2% at 6 weeks (p < 0.029) and by 61.7% at 12 weeks (p < 0.025) in nine of ten patients, with 70% patients having a reduction of at least 50%. Attack intensity was reduced by 38.7% at 6 weeks (p < 0.005) and by 62.6% at 12 weeks (p < 0.004) in ten of ten patients, with 70% of patients having a reduction of at least 50%. Attack duration decreased by 67.2% at 6 weeks (p < 0.001) and by 76.2% at 12 weeks (p < 0.001) in ten of ten patients. Two patients were excluded for reasons unrelated to treatment. Self-assessed general health, physical performance, memory and anxiety also improved by the end of the study. Mig-RL treatment was well tolerated and no adverse events occurred. The remarkable efficacy of Mig-RL in not only reducing the frequency of migraine attacks but also their pain intensity and duration in this trial warrants further investigation of this therapy in a double-blind, randomised, placebo-controlled investigation involving a larger patient population.

Frovatriptan: a review of pharmacology, pharmacokinetics and clinical potential in the treatment of menstrual migraine

Frovatriptan is an orally active 5-hydroxytryptamine (5-HT) receptor agonist which binds with high affinity to 5-HT(1B) and 5-HT(1D) receptors. Earlier clinical trials demonstrated that frovatriptan 2.5 mg is significantly more effective than placebo in the acute management of migraine and its associated symptoms. More recently, frovatriptan was shown to be effective in the management of menstrual migraine. The incidence of menstrual migraine in subjects receiving frovatriptan 2.5 mg twice daily during the six day perimenstrual period was 41% compared with 67% with placebo. Frovatriptan treatment is generally well tolerated. The most commonly reported adverse effects were dizziness, paresthesia, dry mouth, and fatigue. Pharmacologic studies demonstrated that frovatriptan is cerebroselective. Its selectivity for cerebral vessels lessens the potential for undesirable peripheral effects. Frovatriptan has a terminal deposition half-life of approximately 26 hours, which appears to be independent of age, gender, and renal function. This imparts that frovatriptan may be particularly well suited to patients with prolonged migraines and those who suffer migraine recurrence. Frovatriptan does not alter cytochrome P450 (CYP450) isoenzymes, as such it is unlikely to affect the metabolism of other drugs. No dosage adjustments are necessary based on age, renal, or mild to moderate hepatic impairment. Apart from its efficacy in the acute management of migraine, frovatriptan is an effective agent when used as either acute therapy or as intermittent prophylaxis therapy of menstrual migraines, particularly in women who do not respond to conventional therapies.

P.1.e.001 Fusiform gyral volumes over two time points in adolescent-onset schizophrenia

Serotonin 5-HT1A and 5-HT1B/1D receptors control serotonin (5-HT) release and are targets for the pharmacological treatment of psychiatric disorders. We investigated effects of the 5-HT1B/1D antagonist GR127935, the 5-HT1A antagonist WAY 100635 and a combination of both in guinea pigs on the behaviour in the forced swimming test and on extracellular 5-HT in the hippocampus and the prefrontal cortex using in vivo microdialysis. Tissue content of 5-HT, 5-HIAA and 5-HT turnover (ratio 5-HIAA/5-HT) were determined in a sample containing i) the median and dorsal raphe nuclei, ii) the frontal cortex, or iii) the ventral hippocampus ex vivo.Administration of WAY 100635 (0.3–3.0 mg/kg, i.p.) or GR127935 (1.0–10.0 mg/kg, i.p.) or the combination of both delayed immobility in the forced swim test.Systemic administration of WAY 100635 (1 mg/kg i.p.), perfusion with GR127935 (10 μM perfused into the frontal cortex) in the medial prefrontal cortex or the combination of both treatments had no significant effect on extracellular 5-HT.Compared to controls, WAY 100635, GR127935 and the combination thereof, decreased cortical 5-HT (− 30%), increased 5-HIAA and consequently 5-HT turnover in the cortex threefold and the raphe nuclei twofold. WAY 100635 decreased 5-HT in the hippocampus (− 40%), too. WAY 100635 and GR127935 and their combination increased hippocampal 5-HIAA and 5-HT turnover twofold, compared to controls.The results suggest that both 5-HT1 antagonists have subtle effects on 5-HT function under resting conditions; combined treatment has no superior effects compared to solitary treatment.

Antimigraine Drug, Zolmitriptan, Inhibits High-Voltage Activated Calcium Currents in a Population of Acutely Dissociated Rat Trigeminal Sensory Neurons

BackgroundTriptans, 5-HT1B/ID agonists, act on peripheral and/or central terminals of trigeminal ganglion neurons (TGNs) and inhibit the release of neurotransmitters to second-order neurons, which is considered as one of key mechanisms for pain relief by triptans as antimigraine drugs. Although high-voltage activated (HVA) Ca2+ channels contribute to the release of neurotransmitters from TGNs, electrical actions of triptans on the HVA Ca2+ channels are not yet documented.ResultsIn the present study, actions of zolmitriptan, one of triptans, were examined on the HVA Ca2+ channels in acutely dissociated rat TGNs, by using whole-cell patch recording of Ba2+ currents (IBa) passing through Ca2+ channels. Zolmitriptan (0.1–100 μM) reduced the size of IBa in a concentration-dependent manner. This zolmitriptan-induced inhibitory action was blocked by GR127935, a 5-HT1B/1D antagonist, and by overnight pretreatment with pertussis toxin (PTX). P/Q-type Ca2+ channel blockers inhibited the inhibitory action of zolmitriptan on IBa, compared to N- and L-type blockers, and R-type blocker did, compared to L-type blocker, respectively (p < 0.05). All of the present results indicated that zolmitriptan inhibited HVA P/Q- and possibly R-type channels by activating the 5-HT1B/1D receptor linked to Gi/o pathway.ConclusionIt is concluded that this zolmitriptan inhibition of HVA Ca2+ channels may explain the reduction in the release of neurotransmitters including CGRP, possibly leading to antimigraine effects of zolmitriptan.

Disposition and metabolism of almotriptan in rats, dogs and monkeys

Almotriptan is a new highly potent selective 5-HT1B/1D receptor agonist developed for the treatment of migraine, and the disposition of almotriptan in different animal species is now addressed in the current study. Almotriptan was well absorbed in rats (69.1%) and dogs (100%) following oral treatment. The absolute bioavailability was variable reflecting different degrees of absorption and first-pass metabolism (18.7–79.6%). The elimination half-life was short and ranged between 0.7 and 3 h. The main route of elimination of almotriptan was urine with 75.6% and 80.4% of the dose recovered over a 168-h period in rats and dogs, respectively. The γ-aminobutyric acid metabolite formed by oxidation of the pyrrolidine ring was the main metabolite found in urine, faeces, bile, and plasma of rats and in monkey urine. By contrast, the unchanged drug, the indole acetic acid metabolite formed by oxidative deamination of the dimethylaminoethyl group, and the N-oxide metabolite were the main metabolites in dog.

Influence of temperature and gonadal steroids on the ontogenetic expression of brain serotonin 1A and 1D receptors during the critical period of sexual differentiation in tilapia, Oreochromis mossambicus

cDNA sequences of serotonin (5-hydroxytryptamine, 5-HT) 1A and 1D receptors were cloned from the tilapia, Oreochromis mossambicus, brain. The influence of both gonadal steroids and temperature on the ontogenetic expression of brain 5-HT1A and 5-HT1D receptors from days 5 to 15 post-hatch, a critical period of sexual differentiation, was investigated using quantitative real-time reverse transcription-polymerase chain reaction. Neither estrogen nor methyltestosterone had an effect on the ontogenetic expression of 5-HT1A or 5-HT1D receptors. Between days 5 and 10 post-hatch, a critical period for low-temperature-induced feminization, we found no significant difference in the ontogenetic expression of 5-HT1A between exposure to low and elevated temperature. A similar result was found for 5-HT1D. Between days 10 and 15 post-hatch, a critical period for elevated-temperature-induced masculinization, the ontogenetic expression of neither brain 5-HT1A nor 5-HT1D was altered by exposure to elevated temperature. These results suggest that neither brain 5-HT1A nor 5-HT1D plays a critical role in either gonadal steroid- or temperature-induced sexual differentiation.

Activation of α 1D Adrenergic Receptors in the Rat Urothelium Facilitates the Micturition Reflex

Previous studies have revealed that the activation of alpha(1) adrenergic receptors in urothelial cells releases neurotransmitters. We determined if alpha(1D) adrenergic receptors are expressed in the urothelium of the rat bladder and if inhibition of these receptors affects reflex voiding. Female Wistar rats were used in the experiments. Receptor expression was evaluated by Western blot. The effects of receptor activation were studied using cystometrograms, measurement of adenosine triphosphate concentrations in the bladder lumen and afferent nerve recording. The alpha(1D) antagonist naftopidil (0.75 to 1.66 mg/kg) was administered intravenously into the external jugular vein. The expression of alpha(1D) adrenergic receptors was detected in urothelial tissue with Western blot and immunohistochemistry. The alpha(1D) receptor antagonist naftopidil prolonged the intercontraction interval during continuous infusion cystometrograms in conscious rats (143% of the control value) and suppressed the excitatory effect of intravesical infusion of acetic acid (0.1%) on the intercontraction interval (220%). Naftopidil inhibited the bladder afferent nerve activity induced by bladder distention (32.0%) and acetic acid infusion (30.4%), and decreased adenosine triphosphate levels in the bladder perfusate during bladder distention (36.6%). Endogenous catecholamines appear to act on alpha(1D) receptors in the urothelium to facilitate mechanosensitive bladder afferent nerve activity and reflex voiding.

Identification of a potent and selective 5-HT 1B receptor antagonist

An SAR study around the mixed 5-HT 1ABD receptor antagonist SB-272183 found that introduction of cis-2,6-dimethyl substitution onto the piperazine ring was a key structural change, which imparted a combination of both excellent selectivity over the 5-HT 1A and 5-HT 1D receptors and low intrinsic activity. This led to the identification of the selective 5-HT 1B receptor antagonist SB-616234.

Rizatriptan in migraine

The prevalence of migraine is high, affecting a significant proportion of the adult population during their most productive years of life and promoting impairment of their normal daily activities. Although guidelines for the acute treatment of migraine are available, outcome parameters are sometimes still below the expectations of both patients and physicians. Triptans represented an advance in clinical practice and have become the most well-studied class of medication for migraine. These agents present class I evidence for efficacy. However, they differ with regard to several of their clinical parameters, including onset of relief and consistency of response. Rizatriptan is a selective agonist of the 5-hydroxytryptophan1B/1D receptors, with proven superiority over placebo, ergotamine and selected oral triptans, demonstrating a good profile of safety and tolerability.

Effects of 5-HT1B/1D- and 5-HT1A antagonists on 5-HT release and turnover in the CNS

5-HT1A and 5-HT1B/1D receptors regulate serotonin (5-HT) release in the CNS. They are pharmacological targets for treatment of psychiatric disorders.

8-Piperazinyl-2,3-dihydropyrrolo[3,2- g]isoquinolines: Potent, selective, orally bioavailable 5-HT 1 receptor ligands

The novel 8-piperazinyl-2,3-dihydropyrroloisoquinoline template was synthesized in nine steps. The template was N-substituted to give a series of compounds showing binding to human cloned 5-HT 1A, 5-HT 1B and 5-HT 1D receptors with p K i’s greater than 9 and selectivities up to 1000-fold against other serotonin, dopamine and adrenergic receptors. Several compounds were shown to possess weak partial agonist activity in cloned receptors, which translated to antagonism in in vitro studies.

Reactive oxygen species‐dependent TNF‐α converting enzyme activation through stimulation of 5‐HT2Band α1Dautoreceptors in neuronal cells

A major determinant of neuronal homeostasis is the proper integration of cell signaling pathways recruited by a variety of neuronal and non-neuronal factors. By taking advantage of a neuroectodermal cell line (1C11) endowed with the capacity to differentiate into serotonergic (1C115-HT) or noradrenergic (1C11NE) neurons, we identified serotonin (5-hydroxytryptamine, 5-HT)- and norepinephrine (NE)-dependent signaling cascades possibly involved in neuronal functions. First, we establish that 5-HT2B receptors and 1D adrenoceptors are functionally coupled to reactive oxygen species (ROS) synthesis through NADPH oxidase activation in 1C115-HT and 1C11NE cells. This observation constitutes the prime evidence that bioaminergic autoreceptors take part in the control of the cellular redox equilibrium in a neuronal context. Second, our data identify TACE (TNF- Converting Enzyme), a member of a disintegrin and metalloproteinase (ADAM) family, as a downstream target of the 5-HT2B and 1D receptor-NADPH oxidase signaling pathways. Upon 5-HT2B or 1D receptor stimulation, ROS fully govern TNF- shedding in the surrounding milieu of 1C115-HT or 1C11NE cells. Third, 5-HT2B and 1Dreceptor couplings to the NADPH oxidase-TACE cascade are strictly restricted to 1C11-derived progenies that have implemented a complete serotonergic or noradrenergic phenotype. Overall, these observations suggest that 5-HT2B and 1D autoreceptors may play a role in the maintenance of neuron- and neurotransmitter-associated functions. Eventually, our study may have implications regarding the origin of oxidative stress as well as up-regulated expression of proinflammatory cytokines in neurodegenerative disorders, which may relate to the deviation of normal signaling pathways.